Oral Dosage Form Containing A PDE 4 Inhibitor as an Active Ingredient and Polyvinylpyrrolidon as Excipient

ABSTRACT

Dosage forms for oral administration of a PDE 4 inhibitor whose solubility is slight are described. They contain PVP as binder.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical technologyand describes a dosage form for oral administration of a PDE 4 inhibitoras active ingredient in tablet or pellet form for treating diseases suchas asthma or airway obstructions. The invention additionally relates toprocesses for producing the dosage form.

PRIOR ART

Cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically oftype 4) are currently of special interest as a new generation of activeingredients for treating inflammatory disorders, especiallyinflammations of the airways such as asthma or airway obstructions (suchas, for example, COPD=chronic obstructive pulmonary disease). A numberof PDE 4 inhibitors is currently undergoing advanced clinical testing.

In WO00/50011 and WO01/32165, which relate to dosage forms withcontrolled or sustained delivery of a PDE 4 inhibitor, it is pointed outthat unwanted CNS side effects may become manifest on delivery ofcertain PDE 4 inhibitors such as Ariflo® (INN: cilomilast) in higherdosages. WO00/50011 and WO01/32165 see this as being a particular riskwith immediate release dosage forms of the active ingredient andtherefore propose administering the PDE 4 inhibitor Ariflo® (INN:cilomilast) in dosage forms with controlled or sustained release.

U.S. Pat. No. 5,286,494 proposes a dosage form with controlled orsustained release for the PDE 4 inhibitor Rolipram whose solubility isslight. However, production of dosage forms with controlled or sustainedrelease of slightly soluble active ingredients may be technicallycomplicated, reference being made thereto for example in U.S. Pat. No.5,286,494.

The solubility of active ingredients of the PDE 4 inhibitor class inwater and aqueous systems may, depending on the chemical structure, below. Thus, the solubility in water found for the PDE 4 inhibitorN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(INN: roflumilast), which is described in WO95/01338, is only 0.53 mg/lat 21° C. The bioavailability of a medicinal substance dependsessentially on the release of the medicinal substance from thepharmaceutical form. Faster release and dissolution of the medicinalsubstance from the formulation means faster absorption thereof. Withmedicinal substances which are slightly soluble in water, therefore, thebioavailability is frequently limited by the solubility or rate ofdissolution. This makes it very difficult to produce suitable dosageforms.

DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a dosage form fororal administration of PDE 4 inhibitors whose solubility is slight,which form can be produced without great technical complexity, whichtakes account of the low solubility of the PDE 4 inhibitor whosesolubility is slight, and which results in rapid, acceptablebioavailability of the PDE 4 inhibitor whose solubility is slight, so asto attain serum levels which are required in order to obtain the desiredpharmacological effect quickly without side effects becoming manifest.

It has now been found, surprisingly, that this object can be achieved bya dosage form for oral administration of a PDE 4 inhibitor whosesolubility is slight, employing polyvinylpyrrolidone (PVP) as binder forthe dosage form. Compared with dosage forms in which no PVP is employedas binder, the dosage form of the invention shows distinctly improvedpharmacokinetic properties. Thus, in particular in relation to thebioavailability of the PDE 4 inhibitor whose solubility is slight, afaster absorption and thus faster onset of the pharmacological effect isobserved with the dosage forms of the invention compared with dosageforms without PVP. The oral dosage form of the invention is preferably asolid dosage form in tablet or pellet form. It is preferably a solidoral dosage form with immediate release of the active ingredient(immediate release solid oral dosage form).

The invention therefore relates to a dosage form in tablet or pelletform for oral administration of a PDE 4 inhibitor whose solubility isslight, comprising the PDE 4 inhibitor whose solubility is slighttogether with polyvinylpyrrolidone as binder, and one or more othersuitable pharmaceutical excipients.

The PDE 4 inhibitor whose solubility is slight is preferably accordingto the invention a compound from the group of compounds of the formula I

in which either

-   -   R1 is 3-7C cycloalkoxy, 3-7C cycloalkylmethoxy or benzyloxy and    -   R2 is 1-4C alkoxy which is completely or partly substituted by        fluorine,

or

-   -   R1 is 1-4C alkoxy which is completely or partly substituted by        fluorine and    -   R2 is 3-7C cycloalkylmethoxy or benzyloxy,

and

-   -   R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33,        or pyridyl substituted by R34, R35, R36 and R37, where        -   R31 is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl,            1-4C alkyl, 1-4C alkoxy, 1-4C alkoxycarbonyl, 1-4C            alkylcarbonyl, 1-4C alkylcarbonyloxy, amino, mono- or            di-1-4C alkylamino or 1-4C alkylcarbonylamino,        -   R32 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl,            1-4C alkyl or 1-4C alkoxy,        -   R33 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,        -   R34 is hydroxyl, halogen, cyano, carboxyl, 1-4C alkyl, 1-4C            alkoxy, 1-4C alkoxycarbonyl or amino,        -   R35 is hydrogen, halogen, amino or 1-4C alkyl,        -   R36 is hydrogen or halogen and        -   R37 is hydrogen or halogen,

the salts of these compounds and the N-oxides of the pyridines and thesalts thereof.

3-7C Cycloalkoxy is, for example, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C Cycloalkylmethoxy is, for example, cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy andcycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy andcyclopentylmethoxy are preferred.

Examples which may be mentioned of 1-4C alkoxy which is completely orpartly substituted by fluorine are 1,2,2-trifluoroethoxy,2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy and, in particular,1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy anddifluoromethoxy radicals.

Halogen for the purposes of the present invention is bromine, chlorineand fluorine.

1-4C Alkyl represents straight-chain or branched alkyl radicals having 1to 4 carbon atoms. Examples which may be mentioned are butyl, isobutyl,sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

1-4C Alkoxy is a radical which, besides the oxygen atom, contains one ofthe aforementioned 1-4C alkyl radicals. Examples which may be mentionedare the methoxy and ethoxy radicals.

1-4C Alkoxycarbonyl is a carbonyl group to which one of theaforementioned 1-4C alkoxy radicals is bonded. Examples which may bementioned are the methoxycarbonyl (CH₃O—CO—) and ethoxycarbonyl(CH₃CH₂O—CO—) radicals.

1-4C Alkylcarbonyl is a carbonyl group to which one of theaforementioned 1-4C alkyl radicals is bonded. An example which may bementioned is the acetyl radical (CH₃CO—).

1-4C Alkylcarbonyloxy radicals comprise besides the oxygen atom one ofthe aforementioned 1-4C alkylcarbonyl radicals. An example which may bementioned is the acetoxy radical (CH₃CO—O—).

Examples of mono- or di-1-4C alkylamino radicals which may be mentionedare the methylamino, dimethylamino and diethylamino radicals.

An example of a 1-4C alkylcarbonylamino radical which may be mentionedis the acetylamino radical (—NH—CO—CH₃).

Examples of phenyl radicals substituted by R31, R32 and R33 which may bementioned are the radicals 2-acetylphenyl, 2-aminophenyl, 2-bromophenyl,2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,4-diethylamino-2-methylphenyl, 4-bromo-2-trifluoromethylphenyl,2-carboxy-5-chlorophenyl, 3,5-dichloro-2-hydroxyphenyl,2-bromo-4-carboxy-5-hydroxyphenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl,2,6-dibromophenyl, 2-cyanophenyl, 4-cyano-2-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,2-chloro-6-fluorophenyl, 2-hydroxyphenyl, 2-hydroxy-4-methoxyphenyl,2,4-dihydroxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-dimethylaminophenyl,2-methylphenyl, 2-chloro-6-methylphenyl, 2,4-dimethylphenyl,2,6-dimethylphenyl, 2,3-dimethylphenyl, 2-methoxycarbonylphenyl,2-trifluoromethylphenyl, 2,6-dichloro-4-methoxyphenyl,2,6-dichloro-4-cyanophenyl, 2,6-dichloro-4-aminophenyl,2,6-dichloro-4-methoxycarbonylphenyl, 4-acetylamino-2,6-dichlorophenyland 2,6-dichloro-4-ethoxycarbonylphenyl.

Examples of pyridyl radicals substituted by R34, R35, R36 and R37 whichmay be mentioned are the radicals 3,5-dichloropyrid-4-yl,2,6-diaminopyrid-3-yl, 4-aminopyrid-3-yl, 3-methylpyrid-2-yl,4-methylpyrid-2-yl, 5-hydroxypyrid-2-yl, 4-chloropyrid-3-yl,3-chloropyrid-2-yl, 3-chloropyrid-4-yl, 2-chloropyrid-3-yl,2,3,5,6-tetrafluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl,3,5-dibromopyrid-2-yl, 3,5-dibromopyrid-4-yl, 3,5-dichloropyrid-4-yl,2,6-dichloropyrid-3-yl, 3,5-dimethylpyrid-4-yl,3-chloro-2,5,6-trifluoropyrid-4-yl and 2,3,5-trifluoropyrid-4-yl.

Salts suitable for compounds of the formula I—depending on thesubstitution—are all acid addition salts but, in particular, all saltswith bases. Particular mention may be made of the pharmacologicallyacceptable salts of the inorganic and organic acids and bases normallyused in pharmaceutical technology. Pharmacologically unacceptable saltswhich, for example, may be the initial products of the process forpreparing the compounds of the invention on the industrial scale areconverted into pharmacologically acceptable salts by processes known tothe skilled worker. Those suitable on the one hand are water-soluble andwater-insoluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid, or 3-hydroxy-2-naphthoic acid, the acidsbeing employed to prepare the salts in the equimolar ratio of amounts,or one differing therefrom—depending on whether the acid is monobasic orpolybasic and depending on which salt is desired.

On the other hand, salts with bases are also particularly suitable.Examples of basic salts which may be mentioned are lithium, sodium,potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumineor guanidinium salts, once again the bases being employed to prepare thesalts in the equimolar ratio of amounts or one differing therefrom.

Compounds of the formula I to be emphasized are those in which either

-   -   R1 is 3-5C cycloalkoxy, 3-5C cycloalkylmethoxy or benzyloxy and    -   R2 is 1-4C alkoxy which is completely or partly substituted by        fluorine,

or

-   -   R1 is 1-4C alkoxy which is completely or partly substituted by        fluorine and    -   R2 is 3-5C cycloalkylmethoxy or benzyloxy,

and

-   -   R3 is phenyl, pyridyl, phenyl substituted by R31, R32 and R33,        or pyridyl substituted by R34, R35, R36 and R37, where        -   R31 is halogen, cyano, carboxyl, 1-4C alkyl, 1-4C alkoxy or            1-4C alkoxycarbonyl,        -   R32 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,        -   R33 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,        -   R34 is halogen or 1-4C alkyl,        -   R35 is hydrogen or halogen,        -   R36 is hydrogen or halogen and        -   R37 is hydrogen or halogen,

the salts of these compounds, and the N-oxides of the pyridines andsalts thereof.

Compounds of the formula I to be particularly emphasized are those inwhich either

-   -   R1 is 3-5C cycloalkoxy, 3-5C cycloalkylmethoxy or benzyloxy and    -   R2 is 1-4C alkoxy which is completely or partly substituted by        fluorine,

or

-   -   R1 is 1-4C alkoxy which is completely or partly substituted by        fluorine and    -   R2 is 3-5C cycloalkylmethoxy or benzyloxy and    -   R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl,        2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl,        2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl,        2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl,        3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl,        3,5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl,        3-chloro-2,5,6-trifluoropyrid-4-yl,        3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl,

the salts of these compounds, and the N-oxides of the pyridines andsalts thereof.

Preferred compounds of the formula I are those in which

-   -   R1 is difluoromethoxy,    -   R2 is cyclopropylmethoxy and    -   R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl,        2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl,        2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl,        2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl,        3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl,        3,5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl,        3-chloro-2,5,6-trifluoropyrid-4-yl,        3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl,

the salts of these compounds, and the N-oxides of the pyridines andsalts thereof.

A particularly preferred compound of the formula I is the one in which

-   -   R1 is difluoromethoxy,    -   R2 is cyclopropylmethoxy and    -   R3 is 3,5-dichloropyrid-4-yl,

the salts of these compounds, and the N-oxide of the pyridine and saltsthereof.

This compound has the chemical nameN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(INN: roflumilast).

The PDE 4 inhibitor whose solubility is slight is preferably a PDE 4inhibitor with a solubility in water of less than or equal to 100milligram/liter, particularly preferably with a solubility in water ofless than or equal to 1 milligram/liter, at a temperature of 15 to 25°C., in particular at 21° C. This compound is particularly preferably oneof the formula I.

The abovementioned compounds of the formula I and the use of thesecompounds as phosphodiesterase (PDE) 4 inhibitors are described in theinternational patent application WO95/01338.

Further suitable pharmaceutical excipients which may be used in thedosage form of the invention are pharmaceutical excipients such asfillers, additional binders, tablet disintegrants or else lubricants andrelease agents. Other suitable excipients which may be present in thedosage form of the invention are, for example, flavoring substances(such as flavors and sweeteners), buffer substances, preservatives,coloring substances (such as iron oxid yellow or red) or elseemulsifiers. Flavors are usually added in a proportion of from 0.05 to1% by weight. Other flavoring substances by way of example are acidssuch as citric acid, sweeteners such as saccharin, aspartame, cyclamatesodium or maltol, which are added according to the desired result.

The polyvinylpyrrolidone (PVP) employed according to the invention is,in particular, a water-soluble PVP with an average molecular weightabove 2 000, preferably above 20 000. Examples which may be mentionedare Kollidon 12 PF (molecular weight 2 000-3 000), Kollidon 17 PF(molecular weight 7 000-11 000), Kollidon 25 (molecular weight 28 000-34000), Kollidon 30 (molecular weight 44 000-54 000), Kollidon 90 F(molecular weight 1 000 000-1 500 000). PVP of higher molecular weightsuch as, for example, Kollidon 25, Kollidon 30 and Kollidon 90 F may bementioned as preferred.

It is possible if desired to employ in addition to PVP other binderssuch as polyvinyl acetate (e.g. Kollidon® VA 64), gelatin, corn starchmucilage, preswollen starches (Starch 1500),hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (L-HPC).

Fillers suitable according to the invention are fillers such as calciumcarbonate (e.g. MagGran® CC or Destab® 95) and sodium carbonate, sugaralcohols such as mannitol (e.g. Perlitol® or Parteck® M), sorbitol (e.g.Karion®), xylitol or maltitol, starches such as corn starch, potatostarch and wheat starch, microcrystalline cellulose, saccharides such asglucose, lactose (e.g. lactose monohydrate), levulose, sucrose anddextrose. It is also possible if desired to use mixtures thereof. Cornstarch, microcrystalline cellulose and lactose may be mentioned aspreferred.

Examples of suitable lubricants and release agents which may bementioned are sodium stearyl fumarate, magnesium stearate, calciumstearate, stearic acid, talc and colloidal anhydrous silica (Aerosil).

Disintegrants suitable according to the invention are, in particular,insoluble polyvinylpyrrolidone (insoluble PVP, crospovidone),carboxymethylstarch sodium [=sodium starch glycolate], sodiumcarboxymethylcellulose, alginic acid, and starches able to carry out thefunction of a disintegrant (e.g. Starch 1500).

The proportion (in percent by weight based on the finished dosage form)of PDE 4 inhibitor in the dosage form of the invention is usually,depending on the nature of the PDE 4 inhibitor, from 0.01 to 50% byweight. The proportion of PDE 4 inhibitor is preferably up to 20% byweight.

The proportion (in percent by weight based on the finished dosage form)of binder (PVP and, where appropriate, other binders) may preferably beaccording to the invention from 0.5 to 20% by weight. The proportion ofPVP is preferably from 1 to 5% by weight, particularly preferably 2 to3% by weight.

The proportion (in percent by weight based on the finished dosage form)of filler in the tablet of the invention is advantageously from 40 to99% by weight. The proportion of filler is preferably from 60 to 97% byweight.

The proportion (in percent by weight based on the finished dosage form)of disintegrant in the rapidly disintegrating tablet can usually be upto 35% by weight. The proportion of disintegrant is preferably from 2 to20% by weight. The proportion of disintegrant is particularly preferablyfrom 5 to 10% by weight.

The proportion (in percent by weight based on the finished dosage form)of lubricant or release agent in the rapidly disintegrating tablet isusually from 0.1 to 5% by weight. The proportion of lubricant or releaseagent is preferably from 0.3 to 3% by weight. The proportion oflubricant or release agent is particularly preferably from 0.5 to 2% byweight.

In a preferred embodiment of the invention, the dosage form is a tablet.It is preferred for the tablet, besides the PDE 4 inhibitor whosesolubility is slight and PVP, to comprise as further pharmaceuticalexcipients at least one filler and at least one lubricant or releaseagent.

The pharmaceutical preparation of the invention can be produced byprocesses known to the skilled worker for producing tablets and pellets.

In one embodiment of the invention, the pharmaceutical form of theinvention is produced by producing a solid solution of the PDE 4inhibitor whose solubility is slight in the binder PVP as carrier. Thiscan take place for example by the solvent method in which PVP, the PDE 4inhibitor and, where appropriate, other pharmaceutical excipients aredissolved in a suitable solvent, and the solvent is subsequently removedagain by spray drying, normal drying, vacuum drying or freeze-drying. Ithas been found, surprisingly, that production of the solid solution isalso possible by the mixing method in which a PDE 4 inhibitor whosesolubility is slight and, where appropriate, other pharmaceuticalexcipients are vigorously mixed together with PVP.

The invention also relates further to a solid solution of a PDE 4inhibitor whose solubility is slight in the binder PVP as carrier. Asolid solution of the PDE 4 inhibitor in the binder PVP as carrier meansaccording to the invention a solid solution with amorphous structure inwhich the PDE 4 inhibitor is in the form of a molecular dispersion inthe carrier material.

In the event of further processing of a solid solution to tablets orpellets, the solid solution may be processed as active ingredientcomponent together with the filler, binder, disintegrant and lubricantcomponents by production processes familiar to the skilled worker togive the oral dosage forms of the invention.

The invention therefore also relates to a process for producing a dosageform in tablet or pellet form for oral administration of a PDE 4inhibitor, comprising the steps: (a) production of an active ingredientpreparation in the form of a solid solution in PVP of the PDE 4inhibitor whose solubility is slight, (b) production of a mixture of anactive ingredient preparation and pharmaceutical excipients and (c)granulation of the mixture obtained in (b) with an aqueous solution ofPVP.

In the case of dosage forms of the invention in the form of tablets, thegranules obtained in (c) can, after drying and mixing with lubricants orrelease agents, be compressed in a tablet press. In the case of dosageforms of the invention in the form of pellets, the wet granules obtainedin (c) can be processed by the extruder/spheroidizer process to suitablepellets. Alternatively, dispersions/suspensions of an active ingredientpreparation can be applied in the form of a solid solution in PVP of thePDE 4 inhibitor whose solubility is slight in a suitable solvent topellet-like carriers (e.g. nonpareils or HPMC-containing pellets).

In another preferred embodiment of the invention, the dosage form of theinvention is produced by granulating a mixture of active ingredient andpharmaceutical excipients with an aqueous PVP solution, drying thegranules and, if desired, admixing other pharmaceutical excipients. Wetpreparations obtained after granulation can then be further processed topellets and can subsequently be packed into capsules. Dried granulescan—if desired after admixture of other pharmaceutical excipients—aftermixing with a release agent be compressed in a tablet press. Thegranulation preferably takes place in a fluidized bed granulator undersuitable conditions. It is moreover possible if desired for the activeingredient to be admixed to the other pharmaceutical excipients in theform of a trituration with a pharmaceutical excipient (especially afiller). This is particularly preferred when the active ingredientcontent in the dosage form is less than 5% by weight. Such a triturationcan normally be obtained by grinding the active ingredient with apharmaceutical excipient (especially a filler).

The invention therefore also relates to a process for producing a dosageform in tablet or pellet form for oral administration of a PDE 4inhibitor comprising the steps:

-   -   (a) production of a mixture of active ingredient and        pharmaceutical excipients and    -   (b) granulation of the mixture obtained in (a) with an aqueous        solution of PVP.

The dosage form of the invention is particularly preferably produced bygranulation of a mixture of

-   -   (a) PDE 4 inhibitor whose solubility is slight, or a trituration        of the PDE 4 inhibitor whose solubility is slight with corn        starch,    -   (b) corn starch and    -   (c) lactose monohydrate

with an aqueous PVP solution, drying of the granules, mixing of thegranules with a release agent and compression in a tablet press. The PDE4 inhibitor whose solubility is slight is in this case particularlypreferably roflumilast, the salts thereof, the N-oxide of the pyridineand salts thereof.

Alternatively, the dosage form of the invention is particularlypreferably produced by granulation of a mixture of

-   -   (a) PDE 4 inhibitor whose solubility is slight, or a trituration        of the PDE 4 inhibitor whose solubility is slight with corn        starch,    -   (b) corn starch,    -   (c) microcrystalline cellulose and    -   (d) sodium carboxymethylstarch

with an aqueous PVP solution, drying of the granules, mixing of thegranules with a release agent and compression in a tablet press. The PDE4 inhibitor whose solubility is slight is in this case particularlypreferably roflumilast, the salts thereof, the N-oxide of the pyridineand salts thereof.

In a further preferred embodiment of the invention, the dosage form ofthe invention is produced by granulation of a mixture of pharmaceuticalexcipients with a suspension of the active ingredient in an aqueous PVPsolution, drying of the granules and, if desired, admixture of furtherpharmaceutical excipients. The preparations obtained in this way canthen, after mixing with a release agent, be compressed in a tabletpress. The granulation preferably takes place in a fluidized bedgranulator under suitable conditions.

The invention therefore also relates to a process for producing a dosageform in tablet or pellet form for oral administration of a PDE 4inhibitor comprising the steps:

-   -   (a) production of a mixture of pharmaceutical excipients and    -   (b) granulation of the mixture obtained in (a) with a suspension        of the active ingredient in an aqueous solution of PVP.

The dosage form of the invention is particularly preferably produced bygranulation of a mixture of corn starch and lactose monohydrate with asuspension of the PDE 4 inhibitor whose solubility is slight in anaqueous solution of PVP, drying of the granules, mixing of the granuleswith a release agent and compression in a tablet press.

It has surprisingly been found that dosage forms of the inventionproduced employing physical mixtures or triturations of the PDE 4inhibitor whose solubility is slight with a filler (e.g. by grinding,vigorous mixing or extrusion) and subsequent granulation with aqueousPVP solutions, or produced employing granulation suspensions of PDE 4inhibitors in aqueous PVP solutions, have similar advantageousproperties in relation to the bioavailability of the PDE 4 inhibitorwhose solubility is slight as do dosage forms produced by firstproducing solid solutions of PVP and PDE 4 inhibitor. This suggests thatin the production of the dosage forms of the invention based on physicalmixtures or triturations of the PDE 4 inhibitor whose solubility isslight with a filler, which are subsequently granulated with aqueous PVPsolutions, or in whose preparation granulation suspensions of PDE 4inhibitors in aqueous PVP solutions are employed, there are,surprisingly, interactions between PVP and PDE 4 inhibitor whosesolubility is slight, like those occurring in the solid solution of PVPand PDE 4 inhibitor. In the production of the dosage forms of theinvention it is therefore also possible to dispense with the moretechnically elaborate variant of production of a solid solution by thesolvent method.

DESCRIPTION OF THE FIGURE

FIG. 1 shows the time course of the average serum concentration ofroflumilast after oral administration of 0.5 mg (2 tablets eachcontaining 0.25 mg) of roflumilast from dosage forms of the inventioncompared with a dosage form containing no PVP.

The production of tablets and preparations of the invention is describedby way of example below. The following examples explain the invention inmore detail without restricting it.

EXAMPLES

Production of Tablets of the Invention

Example A

Weight Based on a Tablet Containing 0.1 mg of Roflumilast

1. Roflumilast (micronized) 0.100 mg 2. Lactose monohydrate 49.660 mg 3.Corn starch 13.390 mg 4. Polyvidone K90 1.300 mg 5. Magnesium stearate(vegetable) 0.650 mg Total 65.100 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.1 mg.

Example B

Weight Based on a Tablet Containing 0.125 mg of Roflumilast

1. Roflumilast 0.125 mg 2. Lactose monohydrate 49.660 mg 3. Corn starch13.390 mg 4. Polyvidone K90 1.300 mg 5. Magnesium stearate (vegetable)0.650 mg Total 65.125 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.125 mg.

Example C

Weight Based on a Tablet Containing 0.25 mg of Roflumilast

1. Roflumilast 0.250 mg 2. Microcrystalline cellulose 33.900 mg 3. Cornstarch 2.500 mg 4. Polyvidone K90 2.250 mg 5. Sodium carboxymethylstarch(type A) 20.000 mg 6. Magnesium stearate (vegetable) 0.600 mg Total59.500 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2), (5) andthe remaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (6) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 59.5 mg.

Example D

Weight Based on a Tablet Containing 0.25 mg of Roflumilast

1. Roflumilast 0.250 mg 2. Lactose monohydrate 49.660 mg 3. Corn starch13.390 mg 4. Polyvidone K90 1.300 mg 5. Magnesium stearate (vegetable)0.650 mg Total 65.250 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.25 mg.

Example E

Weight Based on a Tablet Containing 0.5 mg of Roflumilast

1. Roflumilast 0.500 mg 2. Lactose monohydrate 49.660 mg 3. Corn starch13.390 mg 4. Polyvidone K90 1.300 mg 5. Magnesium stearate (vegetable)0.650 mg Total 65.500 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.500 mg.

Example F

Weight Based on a Tablet Containing 0.5 mg of Roflumilast

1. Roflumilast 0.500 mg 2. Lactose monohydrate 99.320 mg 3. Corn starch26.780 mg 4. Polyvidone K90 2.600 mg 5. Magnesium stearate (vegetable)1.300 mg Total 130.500 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 130.5 mg.

Example G

Weight Based on a Tablet Containing 2.5 mg of Roflumilast

1. Roflumilast 2.500 mg 2. Microcrystalline cellulose 33.900 mg 3. Cornstarch 2.500 mg 4. Polyvidone K90 2.250 mg 5. Sodium carboxymethylstarch(type A) 20.000 mg 6. Magnesium stearate (vegetable) 0.600 mg Total61.750 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2), (5) andthe remaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on and dried under suitable conditions. (6) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 61.75 mg.

Example H

Production of Tablets Containing 0.1 mg of Roflumilast as ActiveIngredient (Weight for a Batch of 70 000 Tablets)

1. Roflumilast (micronized) 7.000 g 2. Lactose monohydrate 3476.200 g 3.Corn starch 937.300 g 4. Polyvidone K90 91.000 g 5. Magnesium stearate(vegetable) 45.500 g Total 4557.000 g

Production: (1) is mixed with 70 g of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) in purifiedwater is sprayed on. (Spraying pressure: 3 bar; product temperature:28-33° C.; air flow rate in the first third of the spraying process: 100m³/h; air flow rate subsequently during the spraying process: 150 m³/h;inlet air temperature: 40-70° C.; spraying rate: 30-40 g/min). Afterspraying is complete, drying is carried out until the producttemperature reaches 34° C. The granules are passed through a stainlesssteel sieve with a mesh width of 0.8 mm, and the relative surfacemoisture is measured and adjusted to a value in the range 20-50%. (5) isadded to the granules, and the mixture obtained after mixing iscompressed in a tablet press to tablets having an average weight of 65.1mg.

Example I

Production of Tablets Containing 0.25 mg of Roflumilast as ActiveIngredient (Weight for a Batch of 70 000 Tablets)

1. Roflumilast (micronized) 35.000 g 2. Lactose monohydrate 3476.200 g3. Corn starch 937.300 g 4. Polyvidone K90 91.000 g 5. Magnesiumstearate (vegetable) 45.500 g Total 4585.000 g

Production: 19.25 g of (1) are mixed with 192.5 g of (3), and atrituration is produced in a planetary mill. The trituration is puttogether with (2) and the remaining amount of (3) in the productcontainer of a fluidized bed granulation system, and a 5% granulationsolution of (4) in purified water is sprayed on. (Spraying pressure: 3bar; product temperature: 28-33° C.; air flow rate in the first third ofthe spraying process: 100 m³/h; air flow rate subsequently during thespraying process: 150 m³/h; inlet air temperature: 40-70° C.; sprayingrate: 30-40 g/min). After spraying is complete, drying is carried outuntil the product temperature reaches 34° C. The granules are passedthrough a stainless steel sieve with a mesh width of 0.8 mm, and therelative surface moisture is measured and adjusted to a value in therange 20-50%. (5) is added to the granules, and the mixture obtainedafter mixing is compressed in a tablet press to tablets having anaverage weight of 65.5 mg.

Example J

Production of Tablets Containing 0.1 mg of Roflumilast as ActiveIngredient (Weight for a Batch of 70 000 Tablets)

1. Roflumilast (micronized) 7.000 g 2. Lactose monohydrate 3476.200 g 3.Corn starch 937.300 g 4. Polyvidone K90 91.000 g 5. Magnesium stearate(vegetable) 45.500 g Total 4557.000 g

Production: (1) is homogeneously suspended in a granulation solution of(4) in purified water. (2) and (3) are put into the product container ofa suitable fluidized bed granulation system and granulated with thegranulation suspension described above, and then dried. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.1 mg.

Example K

Production of Tablets Containing 0.25 mg of Roflumilast as ActiveIngredient (Weight for a Batch of 70 000 Tablets)

1. Roflumilast (micronized) 35.000 g 2. Lactose monohydrate 3476.200 g3. Corn starch 937.300 g 4. Polyvidone K90 91.000 g 5. Magnesiumstearate (vegetable) 45.500 g Total 4585.000 g

Production: (1) is homogeneously suspended in a granulation solution of(4) in purified water. (2) and (3) are put into the product container ofa suitable fluidized bed granulation system and granulated with thegranulation suspension described above, and then dried. (5) is added tothe granules, and the mixture obtained after mixing is compressed in atablet press to tablets having an average weight of 65.25 mg.

Example L

Weight Based on a Tablet Containing 0.25 mg of Roflumilast

1. Roflumilast 0.250 mg 2. Lactose monohydrate 49.660 mg 3. Potatostarch 10.000 mg 4. Corn starch 3.590 mg 5. PVP 25 1.500 mg 6. Magnesiumstearate (vegetable) 0.650 mg Total 65.650 mg

Production: A dispersion is produced from (4) and water, and (1) ishomogeneously suspended therein. (5) is dissolved in water and added tothe dispersion. (2) and (3) are granulated in a suitable fluidized bedgranulation system with the dispersion under suitable conditions. (6) isadded to this mixture, and the mixture obtained after mixing iscompressed in a tablet press to tablets having an average weight of65.650 mg.

Example M

Weight Based on a Tablet Containing 0.25 mg of Roflumilast

1. Roflumilast 0.250 mg 2. Lactose monohydrate 49.660 mg 3. Corn starch13.390 mg 4. Polyvidone K90 1.300 mg 5. Gelatin 1.300 mg 6. Magnesiumstearate (vegetable) 0.650 mg Total 66.550 mg

Production: (1) is mixed with part of (3), and a trituration is producedin a planetary mill. The trituration is put together with (2) and theremaining amount of (3) in the product container of a fluidized bedgranulation system, and a 5% granulation solution of (4) and (5) inpurified water is sprayed on and dried under suitable conditions. (6) isadded to the granules, and the mixture obtained after mixing iscompressed in a tablet press to tablets having an average weight of66.55 mg.

Example M1

Formulation for Pediatric Use

Weight Based on a Tablet Containing 0.125 mg of Roflumilast

1. Roflumilast 0.125 mg 2. Lactose monohydrate 49.660 mg 3. Corn starch13.390 mg 4. Polyvidone K90 1.300 mg 5. Mannit 32.238 mg 6. Flavor(Tutti Frutti) 0.329 mg 7. PVP (insoluble) 12.895 mg 5. Magnesiumstearate (vegetable) 1.649 mg Total 111.586 mg

The formulation is produced according to a process disclosed above.

Physical Investigations and Comparative Tests with Dosage Forms in whichno PVP was Used as Binder

Example N

The disintegration time and the release of active ingredient weredetermined for a dosage form corresponding to example D.

Disintegration time: the disintegration time was determined using adisintegration tester by the method described in the EuropeanPharmacopoeia.

Result: 7.08 minutes.

Release of active ingredient: the release of active ingredient wasdetermined as described in the US Pharmacopeia (USP XXV; apparatus 2).

Result: 78% of the active ingredient are released after 15 minutes, andquantitative release is observed after 60 minutes.

Example O

Production of a Dosage Form Containing Roflumilast in which no PVP isUsed:

Weight Based on a Tablet Containing 0.25 mg of Roflumilast

1. Roflumilast 0.250 mg 2. Lactose monohydrate 70.300 mg 3. Potatostarch 19.475 mg 4. Corn starch 3.563 mg 5. Sodium carboxymethylstarch(Type A) 1.900 mg 6. Magnesium stearate (vegetable) 0.950 mg Total96.438 mg

Production: A dispersion is produced from (4) and water, and (1) ishomogeneously suspended therein. (2) and (3) are granulated in asuitable fluidized bed granulation system with the dispersion undersuitable conditions. (5) is added to the dry granules, and a homogeneousmixture is produced. (5) is added to this mixture, and the mixtureobtained after mixing is compressed in a tablet press to tablets havingan average weight of 96.438 mg.

Comparative Study

Design: 24 subjects, 3-period changeover, randomized; dose in each case0.5 mg (2 tablets each containing 0.25 mg of roflumilast). The serumconcentration of roflumilast after oral administration of 0.5 mg (2tablets each containing 0.25 mg) of roflumilast was investigated for thefollowing dosage forms:

With PVP as Binder:

Tablet corresponding to example D, referred to as “treatment A”hereinafter.

Tablet corresponding to example K, referred to as “treatment B”hereinafter.

Without PVP as Binder:

Tablet corresponding to example O, referred to as “treatment C”hereinafter.

The results are depicted in FIG. 1. Higher serum levels were observedconsiderably more quickly after oral administration for dosage formswith PVP as binder compared with dosage forms without PVP. The rate ofabsorption is thus distinctly increased for the dosage forms of theinvention.

INDUSTRIAL APPLICABILITY

The dosage forms of the invention can be employed for the treatment andprevention of all diseases regarded as treatable or preventable throughthe use of PDE 4 inhibitors. Selective cyclic nucleotidephosphodiesterase (PDE) inhibitors (specifically of type 4) are suitableon the one hand as bronchial therapeutic agents (for the treatment ofairway obstructions owing to their dilating effect but also owing totheir effect increasing the respiratory rate and respiratory drive) andfor eliminating erectile dysfunction owing to the vasodilating effect,but on the other hand especially for the treatment of disorders,especially of an inflammatory nature, e.g. of the airways (asthmaprophylaxis), of the skin, of the central nervous system, of theintestine, of the eyes and of the joints, which are promoted bymediators such as histamine, PAF (platelet-activating factor),arachidonic acid derivatives such as leukotrienes and prostaglandins,cytokines, interleukins, chemokines, alpha-, beta- and gamma-interferon,tumor necrosis factor (TNF) or oxygen free radicals and proteases. Thepharmaceutical preparations of the invention can therefore be used inhuman and veterinary medicine for example for the treatment andprophylaxis of the following diseases: acute and chronic (especiallyinflammatory and allergen-induced) airway disorders of variousetiologies (bronchitis, allergic bronchitis, bronchial asthma, COPD);dermatoses (especially of a proliferative, inflammatory and allergicnature) such as, for example, psoriasis (vulgaris), toxic and allergiccontact eczema, atopic eczema, seborrhoic eczema, lichen simplex,sunburn, pruritus in the genitoanal region, alopecia areata,hypertrophic scars, discoid lupus erythematosus, follicular andextensive pyodermas, endogenous and exogenous acne, acne rosacea andother proliferative, inflammatory and allergic skin disorders; disordersbased on excessive release of TNF an leukotrienes, e.g. disorders of thearthritic type (rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis and other arthritic states), disorders of the immunesystem (AIDS, multiple sclerosis), types of shock [septic shock,endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS(adult respiratory distress syndrome)] and generalized inflammations inthe gastrointestinal region (Crohn's disease and ulcerative colitis);disorders based on allergic and/or chronic abnormal immunologicalreactions in the region of the upper airways (pharyngeal space, nose)and adjacent regions (paranasal sinuses, eyes), such as, for example,allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergicconjunctivitis and nasal polyps; but also cardiac disorders which can betreated by PDE inhibitors, such as, for example, heart failure, ordisorders which can be treated owing to the tissue-relaxant effect ofPDE inhibitors, such as, for example, erectile dysfunction or colic ofthe kidneys and ureters connected with kidney stones; or else disordersof the CNS such as, for example, depressions or arterioscleroticdementia.

The invention further relates to a method for the treatment of mammals,including humans, suffering from one of the abovementioned diseases. Themethod is characterized by administration of a therapeutically effectiveand pharmacologically suitable amount of a PDE 4 inhibitor to themammalian patient, the PDE 4 inhibitor being present in a dosage form ofthe invention. The disease is preferably asthma or airway obstructions,especially COPD (=chronic obstructive pulmonary disease).

The dosage forms of the invention comprise the PDE 4 inhibitor in thedose customary for the treatment of the particular disease. The dosageof the active ingredient is of the order of magnitude customary for PDEinhibitors, it being possible to administer the daily dose in one ormore dosage units. The normal dose on systemic therapy (oral) is between0.001 mg and 3 mg per kilogram and day. Dosage forms preferred accordingto the invention contain from 0.01 mg to 5 mg of roflumilast, preferablyfrom 0.05 mg to 2.5 mg, particularly preferably 0.1 mg to 0.5 mg ofroflumilast per dosage unit. Examples of pharmaceutical preparations ofthe invention contain 0.1 mg, 0.125 mg, 0.25 mg and 0.5 mg ofroflumilast per dosage unit. Normally, one or more than one dosage unitof the invention is administered once a day. If desired, it is alsopossible for one or more dosage units of the invention to beadministered more than once a day.

1.-11. (canceled)
 12. An immediate release solid dosage form in tabletor pellet form for oral administration ofN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(roflumilast), comprising: (a) between 0.25 and 0.5 mg of roflumilast;(b) a binder; and (c) one or more suitable pharmaceutical excipientsselected from the group consisting of fillers, tablet disintegrants,lubricants, release agents, flavoring substances, buffer substances,preservatives, coloring substances and emulsifiers, whereinapproximately 78% of the roflumilast is released after 15 minutes. 13.The solid dosage form according to claim 12, wherein quantitativerelease of roflumilast is observed after approximately 60 minutes. 14.The solid dosage form according to claim 12, wherein the disintegrationtime of the dosage form is approximately 7 minutes.
 15. The solid dosageform according to claim 12, wherein the dosage form is a tablet.
 16. Thesolid dosage form according to claim 12, wherein said binder is presentin a proportion of about 0.5% to about 20% by weight based on thefinished dosage form.
 17. The solid dosage form according to claim 12,wherein said roflumilast is in the form of a solid solution in saidbinder, said solid solution having an amorphous structure.
 18. The soliddosage form according to claim 12, wherein said roflumilast is in theform of a molecular dispersion in said binder.
 19. The solid dosage formaccording to claim 12, comprising 0.5 mg of roflumilast.
 20. The soliddosage form according to claim 12, wherein said dosage form provides amean T_(max) of less than 1.5 hr.
 21. The solid dosage form according toclaim 20, wherein said mean T_(max) is less than 1 hour.
 22. The soliddosage form according to claim 20, wherein said mean T_(max) is lessthan 30 minutes.
 23. An immediate release solid dosage form in tablet orpellet form for oral administration ofN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(roflumilast), comprising: (a) between 0.25 and 0.5 mg of roflumilast;(b) a binder; and (c) one or more suitable pharmaceutical excipientsselected from the group consisting of fillers, tablet disintegrants,lubricants, release agents, flavoring substances, buffer substances,preservatives, coloring substances and emulsifiers, wherein quantitativerelease of roflumilast is observed after approximately 60 minutes. 24.The solid dosage form according to claim 23, wherein approximately 78%of the roflumilast is released after 15 minutes.
 25. The solid dosageform according to claim 23, wherein the disintegration time of thedosage form is approximately 7 minutes.
 26. The solid dosage formaccording to claim 23, wherein said binder is present in a proportion ofabout 0.5% to about 20% by weight based on the finished dosage form. 27.The solid dosage form according to claim 23, wherein said roflumilast isin the form of a solid solution in said binder, said solid solutionhaving an amorphous structure.
 28. The solid dosage form according toclaim 23, wherein said roflumilast is in the form of a moleculardispersion in said binder.
 29. The solid dosage form according to claim23 comprising 0.5 mg of roflumilast.
 30. The solid dosage form accordingto claim 23, wherein said dosage form provides a mean T_(max) of lessthan 1.5 hr.
 31. The solid dosage form according to claim 30, whereinsaid mean T_(max) is less than 1 hour.
 32. The dosage form according toclaim 30, wherein said mean T_(max) is less than 30 minutes.
 33. Animmediate release solid dosage form in tablet or pellet form for oraladministration ofN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(roflumilast), comprising: (a) between 0.25 and 0.5 mg of roflumilast;(b) a binder; and (c) one or more suitable pharmaceutical excipientsselected from the group consisting of fillers, tablet disintegrants,lubricants, release agents, flavoring substances, buffer substances,preservatives, coloring substances and emulsifiers, wherein thedisintegration time of the dosage form is approximately 7 minutes. 34.The solid dosage form according to claim 33, wherein approximately 78%of the roflumilast is released after 15 minutes.
 35. The solid dosageform according to claim 33, wherein quantitative release of roflumilastis observed after approximately 60 minutes.
 36. The solid dosage formaccording to claim 33, wherein said binder is present in a proportion ofabout 0.5% to about 20% by weight based on the finished dosage form. 37.The solid dosage form according to claim 33, wherein said roflumilast isin the form of a solid solution in said binder, said solid solutionhaving an amorphous structure.
 38. The solid dosage form according toclaim 33, wherein said roflumilast is in the form of a moleculardispersion in said binder.
 39. The solid dosage form according to claim33, wherein said dosage form provides a mean T_(max) of less than 1.5hr.
 40. The solid dosage form according to claim 39, wherein said meanT_(max) is less than 1 hour.
 41. The solid dosage form according toclaim 39, wherein said mean T_(max) is less than 30 minutes.